Sex Differences in Alzheimer’s Disease: Insights From the Multiomics Landscape

Guo, Lei; Zhong, Margaret B.; Zhang, Larry; Zhang, Bin; Cai, Dongming

doi:10.1016/j.biopsych.2021.02.968

Cited by 93 publications

(80 citation statements)

References 102 publications

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“…The APOE-APOC1-TOMM40 region in chromosome 19 was significantly associated with AD in both sexes, although substantial sex-related changes in lipid metabolism may be associated with this region. Emerging data support the role of APOE lipidation and brain lipid transport in the development of AD (Husain et al, 2021). It is evident that estrogen regulates the expression and synthesis of APOE, and APOE facilitates the neuroprotective effects of estrogens and androgens, suggesting the sex hormone-APOE interaction may underlie the sex difference in AD (Gamache et al, 2020).…”

Section: Discussionmentioning

confidence: 95%

“…It is likely that age-by-sex interactions in AD further complicate detecting sex-difference variants. Additionally, there is a likely crucial role for gene-environmental interaction at multiple epigenetic levels for the observed sex differences in AD (Guo et al, 2021). Further systematic studies on epigenomic, gene expression, and immunomic profiling, as well as the inclusion of a larger spectrum of environmental factors, may provide greater insight into the sex heterogeneity underlying AD.…”

Section: Discussionmentioning

confidence: 99%

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Similar Genetic Architecture of Alzheimer’s Disease and Differential APOE Effect Between Sexes

Wang

Rosenthal

Makowski

et al. 2021

Front. Aging Neurosci.

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Sex differences have been observed in the clinical manifestations of Alzheimer’s disease (AD) and elucidating their genetic basis is an active research topic. Based on autosomal genotype data of 7,216 men and 10,680 women, including 8,136 AD cases and 9,760 controls, we explored sex-related genetic heterogeneity in AD by investigating SNP heritability, genetic correlation, as well as SNP- and gene-based genome-wide analyses. We found similar SNP heritability (men: 19.5%; women: 21.5%) and high genetic correlation (Rg = 0.96) between the sexes. The heritability of APOE ε4-related risks for AD, after accounting for effects of all SNPs excluding chromosome 19, was nominally, but not significantly, higher in women (10.6%) than men (9.7%). In age-stratified analyses, ε3/ε4 was associated with a higher risk of AD among women than men aged 65–75 years, but not in the full sample. Apart from APOE, no new significant locus was identified in sex-stratified gene-based analyses. Our result of the high genetic correlation indicates overall similar genetic architecture of AD in both sexes at the genome-wide averaged level. Our study suggests that clinically observed sex differences may arise from sex-specific variants with small effects or more complicated mechanisms involving epigenetic alterations, sex chromosomes, or gene-environment interactions.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Similar Genetic Architecture of Alzheimer’s Disease and Differential APOE Effect Between Sexes

Wang

Rosenthal

Makowski

et al. 2021

Front. Aging Neurosci.

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“…Finally, DNA replication stress appears to underlie CIN in the Alzheimer's disease brain, allowing a theoretical link between two major hypotheses of the disease: the amyloid hypothesis and cell cycle hypothesis [50]. These data on genome/chromosome behavior in the Alzheimer's disease brain have been commonly correlated with disease phenotype and peculiarities (e.g., sex differences) [44,45,51]. In summary, despite the debates concerning the contribution of brain aging to the pathophysiology of Alzheimer's disease, one has to admit the involvement of CIN, which mediates aging in mitotic tissues and initiates from aging-related alterations to cellular homeostasis, in the pathogenic cascade.…”

Section: Cin In the Diseased Brain: An Aging Perspectivementioning

confidence: 99%

“…At this point, the involvement of X-chromosome-specific aneuploidy (X-chromosome-specific instability) may help to explain sex differences in the aging of the healthy and diseased (Alzheimer's disease) brain. More precisely, increased rates of X chromosome loss (specific for female karyotypes) in the Alzheimer's disease brain [46] might specifically contribute to the disease course in females [51,75]. X-chromosome-specific aneuploidy may not be a unique type of CIN contributing to sex differences in the Alzheimer's disease brain [35].…”

Section: Cin In the Aged Brain: The Shape Of Things To Comementioning

confidence: 99%

Chromosome Instability, Aging and Brain Diseases

Iourov

Yurov

Vorsanova

et al. 2021

Cells

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Chromosome instability (CIN) has been repeatedly associated with aging and progeroid phenotypes. Moreover, brain-specific CIN seems to be an important element of pathogenic cascades leading to neurodegeneration in late adulthood. Alternatively, CIN and aneuploidy (chromosomal loss/gain) syndromes exhibit accelerated aging phenotypes. Molecularly, cellular senescence, which seems to be mediated by CIN and aneuploidy, is likely to contribute to brain aging in health and disease. However, there is no consensus about the occurrence of CIN in the aging brain. As a result, the role of CIN/somatic aneuploidy in normal and pathological brain aging is a matter of debate. Still, taking into account the effects of CIN on cellular homeostasis, the possibility of involvement in brain aging is highly likely. More importantly, the CIN contribution to neuronal cell death may be responsible for neurodegeneration and the aging-related deterioration of the brain. The loss of CIN-affected neurons probably underlies the contradiction between reports addressing ontogenetic changes of karyotypes within the aged brain. In future studies, the combination of single-cell visualization and whole-genome techniques with systems biology methods would certainly define the intrinsic role of CIN in the aging of the normal and diseased brain.

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“…Only male mice were used, as there were no sex differences in EFV treatment effects on the brain sterol profile and animal performance in behavioural tasks [13,20]. However, we acknowledge that women are known to be more vulnerable to Alzheimer's disease than men and that humans have sex differences in terms of the hallmarks and other manifestations of this disease [23,24]. Mice were selected from the pool of all available animals and randomly assigned to either the control or treatment group, which were matched by size, age (3 months old) and sex.…”

Section: Animalsmentioning

confidence: 99%

Brain Acetyl-CoA Production and Phosphorylation of Cytoskeletal Proteins Are Targets of CYP46A1 Activity Modulation and Altered Sterol Flux

et al. 2021

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Cholesterol and 24-hydroxycholesterol are the most abundant brain sterols and represent the substrate and product, respectively, of cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme. CYP46A1 controls cholesterol elimination and turnover in the brain, the two processes that determine the rate of brain sterol flux through the plasma membranes and thereby the properties of these membranes. Brain sterol flux is decreased in Cyp46a1−/− mice compared to wild-type mice and increased in 5XFAD mice (a model of Alzheimer’s disease) when they are treated with a small dose of efavirenz, a CYP46A1 activator. Herein, we first assessed the brain proteome (synaptosomal fractions) and phospho-proteome (synaptosomal fractions and brain homogenates) of efavirenz-treated and control 5XFAD mice. Then, based on the pattern of protein abundance change, we conducted acetyl-CoA measurements (brain homogenates and mitochondria) and metabolic profiling (brain homogenates). The phospho-proteomics datasets were used for comparative analyses with the datasets obtained by us previously on mice with the same changes (efavirenz-treated and control 5XFAD mice from a different treatment paradigm) or with changes in the opposite direction (Cyp46a1−/− vs wild-type mice) in brain sterol flux. We found that CYP46A1 activity or the rate of brain sterol flux affects acetyl-CoA-related metabolic pathways as well as phosphorylation of cytoskeletal and other proteins. Knowledge of the key roles of acetyl-CoA and cytoskeletal phosphorylation in cell biology expands our understanding of the significance of CYP46A1-mediated cholesterol 24-hydroxylation in the brain and provides an additional explanation for why CYP46A1 activity modulations are beneficial in mouse models of different brain diseases.

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Sex Differences in Alzheimer’s Disease: Insights From the Multiomics Landscape

Cited by 93 publications

References 102 publications

Similar Genetic Architecture of Alzheimer’s Disease and Differential APOE Effect Between Sexes

Similar Genetic Architecture of Alzheimer’s Disease and Differential APOE Effect Between Sexes

Chromosome Instability, Aging and Brain Diseases

Brain Acetyl-CoA Production and Phosphorylation of Cytoskeletal Proteins Are Targets of CYP46A1 Activity Modulation and Altered Sterol Flux

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